We investigated whether CDK5, in addition to its direct effects on HCC cells, also has anti-angiogenic effects in HCC, and identified the underlying mechanism: we demonstrate that CDK5 stabilizes HIF-1α, a master regulator of angiogenesis, by phosphorylation at serine 687 in endothelial and liver cancer cells, and proof the potential of CDK5 as a new target for anti-angiogenic HCC therapeutics by reducing vascularization in tumors of different murine HCC models through pharmacological or genetic inhibition of CDK5. This evidence concerns the gene HIF1A and hepatocellular carcinoma.